Tourette syndrome (TS) is a common, hereditary, neuro-behavioral disorder characterized by motor and vocal tics. Autism is a trait of three sets of symptoms: (1) a profound failure to develop social relationships; (2) defective speech and language; and (3) ritualistic or compulsive behavior.
The symptoms of TS and its related disorders fit a model in which the frontal lobe and limbic system in the brain are disinhibited by a relative deficiency in brain serotonin and tryptophan.
Like TS, autism and MR are neurological disorders. The areas of the brain involved in autism and MR, the frontal lobe and limbic system, are often the same as those involved in TS. Unlike TS where both brain serotonin and tryptophan levels tend to be low, in autism and MR each is often significantly elevated.
Tryptophan-2,3 dioxygenase (tryptophan oxygenase, tryptophan pyrrolase) is considered primarily to be a liver enzyme. However, the same or a very similar enzyme, indoleamine 2,3 dioxygenase is also present in the brain, intestines and other organs. See Gal, E. M. and Sherman, A. D., "L-kynurenine: its synthesis and possible regulatory function in brain", Neurochem. Res. 5:223-239 (1980).
Table 1 depicts several apparent differences between the functions of these enzymes. See Hayaishi, O., "Properties and function of indoleamine 2,3-dioxygenase", J. Biochem 79:13p-21p (1976); Gal, E. M., "Cerebral tryptophan-2,3-dioxygenase (pyrrolase) and its induction in rat brain" J. Neurochem 22:861-863 (1974); and Gal, E. M. and Sherman, A. D., "L-kynurenine: its synthesis and possible regulatory function in brain", Neurochem. Res. 5:223-239 (1980).
TABLE 1 ______________________________________ Tryptophan Indoleamine 2,3-dioxygenase 2,3-dioxygenase ______________________________________ Similarities Substrate L-tryptophan L-tryptophan Product N-formyl N-formyl kynurenine kynurenine Type of protein heme heme Inducible by tryptophan yes yes Differences Location liver brain and many other organs Type of oxygen used O.sub.2 O--O.sup.- Other substrates none D-tryptophan 5-hydroxy- tryptophan serotonin melantoin Inducible by cortisol yes no ______________________________________
It is not known whether these differences are due to the presence of the enzyme in a different form in different tissues or to the fact that the enzymes are produced by different genes. For the purposes of this invention, it is unnecessary to determine whether one or two genes is implicated. A reasonable possibility is that the two forms of TO (liver and intestine-brain) represent alternate modes of transcription or mRNA processing of the human TO gene. Unless separately identified, the liver and brain-intestine enzymes are referenced collectively herein as tryptophan oxygenase or TO.
If TO were present only in the liver, then the level of tryptophan in the brain would be almost completely dependent on the blood level of tryptophan and of the compounds that compete for its transport across the blood brain barrier. However, as FIG. 1 shows, tryptophan oxygenase activity is also present in the brain where it is effective to siphon off some of the tryptophan after brain entry and before it is converted to serotonin.
In rats, under normal conditions 70% of the brain tryptophan is converted to serotonin and 30% to brain kynurenine. Gal, E. M. and Sherman, A. D., "L-kynurenine: its synthesis and possible regulatory function in brain", Neurochem. Res. 5:223-239 (1980). Even a moderate increase in brain tryptophan oxygenase could markedly change this ratio and lower the level of brain serotonin. Significant changes in the breakdown of tryptophan in the brain may thus occur concurrently with only moderate changes in the blood tryptophan and serotonin.
In humans, serotonin and tryptophan levels are apparently interdependent, serotonin level abnormalities being a consequence of tryptophan level abnormalities. As FIG. 2 shows, human brain tryptophan can take two major metabolic pathways, i.e., 90% conversion to kynurenine and 10% conversion to serotonin. TO activity is the rate limiting step in the degradation of tryptophan to kynurenine.
Because TO is implicated in both TS and autism, fairly subtle changes in the level of the enzyme would be expected to significantly affect serotonin production. The TO level may be increased in TS and decreased in autism. However, since some autistic children have low levels of serotonin and some TS patients have high levels, the basic defect in both may be a dysregulation (too high or too low) of serotonin.
More particularly, FIG. 3 indicates that the genetic defect in TS related disorders may be either a duplication or a mutation of the TO gene resulting in high levels of hyperinducability, whereas in autism and some forms of MR the TO gene is either defective or deleted.
Since the serotonin levels in some severe mental retardation are even higher than those in autism, it is likely that the genetic defect causing the elevated serotonin is also more severe and may represent a deletion of the TO gene. By contrast, in TS, the TO genes are duplicated or otherwise mutated so the amount of enzyme is increased.
In genetic terms the most detrimental thing that can be done to a gene is to delete it. A single base change mutation within the gene may have no effect, a mild effect or a significant effect on the function of the enzyme that gene makes. Table 2 presents some possible genotypes and phenotypes as a guide to the basic idea. A deletion of a TO gene is termed TO 0, a base pair substitution mutation causing decreased function of TO is termed TO -, a normal gene will be termed TO + and a duplicated gene, or a gene with a mutation causing increased levels or increased efficiency of the tryptophan oxygenase enzyme, is termed TO ++.
TABLE 2 ______________________________________ Effect on Type of Blood Defect Genotype Serotonin Result ______________________________________ None TO +/TO + Normal Normal Levels Deleted/ TO 0/TO 0 Extremely Severe M.R. Deleted High .+-. Autism Deleted/ TO 0/TO - Very High Autism with Mutant M.R. Mutant/ TO -/TO - High Autism Mutant Some TS Mutant TO 0/TO + Moderately Normal or or Deleted/ TO -/TO + High Mild Autism Normal Some TS Mutant or TO ++/TO + Low TS Dup/Normal Serotonin Some Autism Normal Mutant or Dup/ TO ++/TO ++ Low Homozygous Mutant or Dup Serotonin Grade 3 TS Some Autism ______________________________________
Hence, mutations of the human TO gene which result in decreased activity of the TO gene are likely to be involved in some cases of the autism or autism with mental retardation. These mutations would be various heterozygous or homozygous combinations of deletions or base pair mutations affecting activity or function of the human TO gene or genes.
In contrast, mutations of the human TO gene which result in increased activity, or increased inducability or increased efficiency of the TO gene are likely to be involved in Tourette syndrome and many of the wide range of behaviors associated with the TS spectrum of behaviors. These mutations include various heterozygous or homozygous combinations of gene duplications, or mutations of the regulatory or structural sequences of the human TO gene or genes.
Because the defects are enzyme deficiencies, the autism and MR disorders are autosomal recessive. By contrast, for TS because the enzyme level is apparently increased, the trait is autosomal dominant or semi-dominant.
These examples are meant to be an approximation. An abnormal serotonin level (too high or too low) may cause either autism or TS or autism and TS. Many cases of both occurring in the same patient have been described.